Boxed warning

An exemplary boxed warning, as seen in context, in FDA's Challenges and Issues with Safety-Related Information in the Prescribing Information slide deck. For emphasis, the text is bolded and surrounded by a black outline.

In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that it is formatted with a "box" or border around the text ^[1] to emphasize its importance. ^[2] The FDA can require a pharmaceutical company to place a boxed warning. It is the strongest warning that the FDA requires, and signifies that medical studies indicate that the drug carries a significant risk of preventable, serious or even life-threatening adverse effects. ^{[2] [3]}

Economists and physicians have thoroughly studied the effects of FDA boxed warnings on prescription patterns. It is not necessarily true that a physician and patient will have a conversation about a drug's boxed warning after it is issued. ^[4] For instance, an FDA-mandated boxed warning decreased rosiglitazone use by 70%, but that still meant 3.8 million people were given the drug. Later research indicated that after receiving an FDA advisory, there was a decrease in rosiglitazone use, due to a combined effect of media exposure, advisory, and scientific publications, whereas pioglitazone (with a similar advisory but less media exposure) did not similarly decrease in use. ^[5]

Examples

Boxed warnings on drugs have received increased media attention in the United States since 2004. Among some of the more widely covered stories:

• In October 2004, the FDA began requiring that boxed warnings be placed on all antidepressant medications, warning they may result in an increased risk of suicidal tendencies in children and adolescents. In May 2006, the boxed warning was expanded to young adults aged 18–24 years old. ^{[6] [7]}
• As of November 17,2004 ^[update] , the FDA has required a boxed warning on the Depo-Provera contraceptive injection, due to the risk of significant loss of bone density with long-term use. ^[8]
• In April 2005, FDA advisors requested that Pfizer place a boxed warning on their non-steroidal anti-inflammatory drug Celebrex (celecoxib) for cardiovascular and gastrointestinal risks. ^{[9] [10]}
• In 2005, the FDA issued a boxed warning regarding the risk of atypical antipsychotics being prescribed among elderly patients with dementia. This advisory was associated with a decrease in use of antipsychotics, especially in elderly patients with dementia. ^[11]
• As of 2006 ^[update] , natalizumab (marketed as Tysabri) received a boxed warning on its packaging due to increased risk of developing progressive multifocal leukoencephalopathy (PML). Tysabri was pulled from the market in 2004, shortly after its introduction, after three cases of the rare disease were linked to its use. PML has affected approximately 212 Natalizumab recipients in 2012 (or 2.1 in every 1000 patients). ^[12] Tysabri is now distributed under a controlled prescription program called TOUCH (Tysabri Outreach: Unified Commitment to Health). ^[13]
• As of October 9,2006 ^[update] , the FDA added a boxed warning to the anticoagulant warfarin due to the risk of bleeding to death. ^[14]
• In February 2006, the FDA's Drug Safety and Risk Management Advisory Committee voted to include boxed warnings on methylphenidate formulations used to treat attention deficit hyperactivity disorder, such as Ritalin (methylphenidate), due to possible cardiovascular side-effects. ^[15] A month later, the agency's Pediatric Advisory Committee effectively rejected recommending boxed warnings for both cardiovascular and psychiatric adverse effects. ^{[16] [17]}
• On November 14, 2007, the FDA added a boxed warning to the diabetes medication Avandia (rosiglitazone), citing the risk of heart failure or heart attack to patients with underlying heart disease, or are at a high heart attack risk. ^[18]
• On July 8, 2008, the FDA ordered a boxed warning on certain antibiotic medications containing fluoroquinolone, which has been linked to tendon ruptures and tendinitis. Included were the popular drugs Cipro (ciprofloxacin), Levaquin (levofloxacin), Avelox (moxifloxacin), Noroxin (norfloxacin) and Floxin (ofloxacin). ^[19]
• On July 1, 2009, the FDA required Chantix (varenicline) to carry a boxed warning due to public reports of side effects including depression, suicidal thoughts, and suicidal actions. As of 2016 ^[update] , the warning has been removed on the basis of updated evidence. ^[20]
• On October 27, 2010, the FDA issued a boxed warning regarding the use of Metacam (meloxicam) oral suspension in cats in the United States. Meloxicam is a non-steroidal anti-inflammatory drug that is approved in the U.S. for a single post-operative injection in cats. ^[21]
• As of May 2013 ^[update] , the FDA issued a boxed warning regarding the use of thyroid hormone stimulating agents in treatment of obesity. ^[22] Data does not indicate any benefits to using these agents for weight loss. Data does indicate an increased risk of life-threatening cardiovascular events when high levels of these agents are used in hypothyroid populations. Euthyroid populations demonstrate increased CV risk at clinical doses. Hypothyroid agents should not be used in combination with sympathomimetic agents including: stimulants, and diet pills, due to increased CV risks.
• In July 2013, the FDA issued a boxed warning for the antimalarial drug mefloquine, noting the drug's adverse neuropsychiatric side effects, and emphasizing neurological effects from the drug could "occur at any time during drug use, and can last for months to years after the drug is stopped or can be permanent". ^[23]

In other jurisdictions

For broader coverage of this topic, see Medication package insert § Sections of the Prescribing Information.

In China, a warning text (警示语) may be added to a package insert, either voluntarily by the manufacturer or at the request of NMPA (formerly CFDA, the Chinese counterpart of FDA). Although no formatting requirement is found in law, the typical formatting is similar to the American counterpart with boxed text at the top of the insert. The CFDA/NMPA has used its power to mandate a warning on fluoroquinolones, ceftriaxone, aciclovir, and pioglitazone. ^[24]

Health Canada terms its version of boxed warnings "serious warnings and precautions box". ^[25] The formatting is similar to the US counterpart; an example for Paxlovid can be seen on Pfizer's website. ^[26]

References

1. "The heading and the summary must be contained within a box and bolded." 21CFR201.57 Subpart B (a)(4)
2. "Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products — Content and Format" (PDF). Guidance for industry. Even in the context of clinical research, human subjects are often not informed about the risks included in boxed warnings for drugs they are being given. For protocols involving drugs with boxed warnings, 63% of consent forms did not disclose 1 or more boxed warning risks. Warnings and precautions, contraindications, and boxed warning sections of labeling for human prescription drug and biological products—content and format. U.S. Food and Drug Administration. Archived from the original (PDF) on June 17, 2009. Retrieved February 21, 2010.
3. "Antidepressant Medications for Children and Adolescents: Information for Parents and Caregivers". National Institute of Mental Health. Archived from the original on March 1, 2010.
4. Shah ND, Montori VM, Krumholz HM, Tu K, Alexander GC, Jackevicius CA (November 2010). "Responding to an FDA warning--geographic variation in the use of rosiglitazone". The New England Journal of Medicine. 363 (22): 2081–2084. doi:10.1056/NEJMp1011042. PMID   21083379.
5. Cohen A, Rabbani A, Shah N, Alexander GC (April 2010). "Changes in glitazone use among office-based physicians in the U.S., 2003-2009". Diabetes Care. 33 (4): 823–825. doi:10.2337/dc09-1834. PMC   2845035 . PMID   20103549.
6. Fornaro M, Anastasia A, Valchera A, Carano A, Orsolini L, Vellante F, et al. (2019). "The FDA "Black Box" Warning on Antidepressant Suicide Risk in Young Adults: More Harm Than Benefits?". Frontiers in Psychiatry. 10: 294. doi: 10.3389/fpsyt.2019.00294 . PMC   6510161 . PMID   31130881. On October 2004, the FDA required a so-called boxed warning for antidepressant drugs of any class. That warning became effective in January 2005. In 2006, the FDA warning extended to young adults aged up to 25 years, an announcement that followed a slew of media reports about the link between antidepressant drug use and suicide, possibly culminating in an exaggerated alarmist message.
7. Ho D (June 2012). "Antidepressants and the FDA's black-box warning: determining a rational public policy in the absence of sufficient evidence". The Virtual Mentor. 14 (6): 483–488. doi:10.1001/virtualmentor.2012.14.6.pfor2-1206. PMID   23351264.
8. "Black Box Warning Added Concerning Long-Term Use of Depo-Provera Contraceptive Injection". Food and Drug Administration . Archived from the original on August 9, 2007. Retrieved August 15, 2007.
9. "COX-2 Selective (includes Bextra, Celebrex, and Vioxx)". U.S. Food and Drug Administration. April 7, 2005. Archived from the original on September 28, 2019. Retrieved January 2, 2024.
10. Corbett J (August 2, 2005). "Celebrex to Get 'Black Box' Label on Heart Risks". The Wall Street Journal. Retrieved January 2, 2024.
11. Dorsey ER, Rabbani A, Gallagher SA, Conti RM, Alexander GC (January 2010). "Impact of FDA black box advisory on antipsychotic medication use". Archives of Internal Medicine. 170 (1): 96–103. doi:10.1001/archinternmed.2009.456. PMC   4598075 . PMID   20065205. Archived from the original on July 27, 2011.
12. Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, et al. (May 2012). "Risk of natalizumab-associated progressive multifocal leukoencephalopathy". The New England Journal of Medicine. 366 (20): 1870–1880. doi: 10.1056/NEJMoa1107829 . PMID   22591293.
13. "TOUCH Program". TOUCH On-Line. Biogen Idec. Retrieved September 8, 2016.
14. "Black Box for Warfarin" . Retrieved August 15, 2007.
15. "Strongest warning suggested for ADHD drugs". CNN. Associated Press. February 10, 2006. Archived from the original on August 18, 2007. Retrieved August 15, 2007.
16. "'Black Box' ADHD Drug Warning Rejected". CBS News . March 22, 2006. Retrieved August 15, 2007.
17. "MINUTES OF THE PEDIATRIC ADVISORY COMMITTEE" (PDF). FDA . March 22, 2006. Archived from the original on April 4, 2017. Retrieved August 15, 2007. The committee members were asked if they felt that based on the data for the pediatric population, there was a need for a boxed warning regarding cardiovascular risks. None on the committee expressed a need for this.
18. "Glaxo's Avandia to carry heart-attack warning". MarketWatch . November 14, 2007. Archived from the original on January 12, 2008. Retrieved November 14, 2007.
19. "FDA orders 'black box' label on some antibiotics". CNN. July 8, 2008. Retrieved July 8, 2008.
20. FDA. "Public Health Advisory: FDA Requires New Boxed Warnings for the Smoking Cessation Drugs Chantix and Zyban". Food and Drug Administration . Archived from the original on October 19, 2010. Retrieved July 1, 2009.
21. "FDA Announces Addition of Boxed Warning to METACAM® (meloxicam) Labels". FDA . October 27, 2010. Archived from the original on October 30, 2010.
22. "Thyrolar (liotrix) dosing, indications, interactions, adverse effects, and more".
23. "FDA Drug Safety Communication: FDA approves label changes for antimalarial drug mefloquine hydrochloride due to risk of serious psychiatric and nerve side effects". July 29, 2013. Archived from the original on August 1, 2013.
24. Lan H, Jun-yi Z (2014). 国内外药品说明书和标签管理中有关警示语的比较研究 [Comparison of Related Content of Warnings in Drug Labels and Package Inserts at Home and Abroad](PDF). 中国药房. 33. doi:10.6039/j.issn.1001-0408.2014.33.29 (inactive July 1, 2025).
25. Alshammari TM, Devadasu VR, Rathnam RP (December 2017). "Comparison of the safety information on drug labels in three developed countries: The USA, UK and Canada". Saudi Pharmaceutical Journal. 25 (8): 1103–1107. doi:10.1016/j.jsps.2017.07.006. PMC   6111122 . PMID   30166896.
26. "PAXLOVID". Pfizer Medical Information - Canada.

External links

• Black Box Warnings by FormWeb.